Isatin derivatives, a novel class of transthyretin fibrillogenesis inhibitors

González, Asensio; Quirante, Josefina; Nieto, Juan Miguel; Almeida, Maria Rosário; Saraiva, Maria João; Planas, Antoni; Arsequell, Gemma; Valencia, Gregorio

doi:10.1016/j.bmcl.2009.03.004

Cited by 48 publications

(36 citation statements)

References 20 publications

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“…The isatin molecule (1H-indole-2,3-dione) is a versatile moiety that displays diverse biological activities, including anticancer activity (Pandeya et al, 1999;Cane et al, 2000;Torres et al, 2004;Pandeya et al, 2005;Abadi et al, 2006;Vine et al, 2007a, b;Uddin et al, 2007;Hung et al, 2008;González et al, 2009;Sirisoma et al, 2009). The synthetic flexibility of isatin led to synthesis of a variety of substituted derivatives; however, the susceptibility of isatin to attack by nucleophiles at C3 resulted in the generation of a large number of 3-substituted isatins in particular (Bramson et al, 2001;Andreani et al, 2005;Chen et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and QSAR study of novel 2-(2,3-dioxo-2,3-dihydro-1H-indol-1-yl)-N-phenylacetamide derivatives as cytotoxic agents

Modi¹,

Shah

Patel

et al. 2010

Med Chem Res

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This study deals with the synthesis of novel 2-(2,3-dioxo-2,3-dihydro-1H-indol-1-yl)-N-phenylacetamide derivatives (6a-j) from isatin (3) and 5,7-dibromoisatin (4). All newly synthesized compounds were characterized using IR, 1 H NMR, MS, and elemental analysis followed by evaluation of their cytotoxic activity by XTT assay on breast cancer cell line MCF-7 and non-cancer African green monkey cell line VERO. Correlation study for QSAR and in vitro assay was performed. The outcomes indicated that electron withdrawing substitutions at para position of phenyl ring and 5, 7 positions of isatin ring and increasing lipophilicity of the compound increased the cytotoxic activity. The 2-(5,7-dibromo-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)-N-(4-nitrophenyl)acetamide (6b) was found to be the most active compound in the series and demonstrated higher selectivity toward MCF-7 cell line. The IC 50 values were 1.96 and 1.90 lM for test compound (6b) and vinblastin (reference drug), respectively. This indicates compound (6b) may possess equipotent cytotoxic activity to vinblastine. The compound (6b) is particularly promising, since it could kill cancer cells 19-20 times more effectively than the non-cancer cells. This property of (6b) may enable us to effectively control tumors with low side effects. Hence, we propose that 2-(5,7-dibromo-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)-N-(4-nitrophenyl)acetamide may be used as lead for further development.

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Section: Introductionmentioning

confidence: 99%

Design, synthesis, and QSAR study of novel 2-(2,3-dioxo-2,3-dihydro-1H-indol-1-yl)-N-phenylacetamide derivatives as cytotoxic agents

Modi¹,

Shah

Patel

et al. 2010

Med Chem Res

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“…Until recently, the most potent and selective agents were the biphenyls, 2-phenylbenzoxazoles and dibenzofurans. Most recently, additional agents, including isatin and b -aminoxypropionic acid linked aryl or fl uorenyl derivatives, have been identifi ed and characterized (Gonzalez et al 2009 ;Palaninathan et al 2009). …”

Section: Transthyretin (Ttr) Amyloidosismentioning

confidence: 98%

Strategies for Inhibiting Protein Aggregation: Therapeutic Approaches to Protein-Aggregation Diseases

Lanning

Meredith

2011

Non-Fibrillar Amyloidogenic Protein Assemblies - Common Cytotoxins Underlying Degenerative Diseases

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Self-aggregation of proteins and peptides is at the root of many diseases, especially neurodegenerative diseases. These conditions include Alzheimer's disease, Huntington's disease, Parkinson's disease, type-2 diabetes mellitus, and transmissible spongiform encephalopathies, which are associated with self-aggregation of amyloid b -protein (A b ), huntingtin, a -synuclein, islet amyloid polypeptide, and the prion protein, respectively. The list of diseases for which protein/peptide aggregation is the root cause is ever expanding. There does not appear to be a single biochemical mechanism by which proteins and peptides self-associate, or a single pathogenic mechanism to explain all protein-/peptide-aggregation diseases. Nevertheless, inhibition of protein self-aggregation remains a potential target for therapeutic intervention. Beyond therapy, inhibitors of protein self-aggregation can serve as tools to help us understand the mechanisms by which aggregation occurs and harms cells. In this chapter, we examine select examples of inhibitors of protein aggregation. We have divided aggregating proteins/peptides into two types: (1) Proteins that have an unstable tertiary structure, that unfold under cellular stress, or that fail to fold correctly during biosynthesis. This instability leads to persistence of unfolded domains that can act as a nidus for self-association. (2) Peptides or proteins (or protein domains) that cannot fold at all, or fold only in the presence of a bound ligand. Examples of the fi rst group include transthyretin, the mammalian prion protein, and certain point-mutant forms of lysozyme or a 1-antitrypsin. In general, self-aggregation of these proteins results from exposure of normally buried hydrophobic residues to aqueous media. Examples of the second group include A b , islet amyloid polypeptide, and calcitonin. Within the second group, we also include proteins that are "peptide-like" in having domains with no unique, stable

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“…tained by a calorimetric experiment (ITC), [21] was used. These theoretical K i 's were needed to carry out the prospective LEI analysis in the nBEI-SEI optimization plane ( Figure 5).…”

Section: Lei Prospective Mapmentioning

confidence: 99%

Retrospective Mapping of SAR Data for TTR Protein in Chemico‐Biological Space Using Ligand Efficiency Indices as a Guide to Drug Discovery Strategies

Blasi

Arsequell

Valencia

et al. 2011

Molecular Informatics

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We have previously reported the design and synthesis of ligands that stabilize Transthyretin protein (TTR) in order to obtain therapeutically active compounds for Familial Amyloid Polyneuropathy (FAP). We are hereby reporting a drug design strategy to optimize these ligands and map them in Chemico-Biological Space (CBS) using Ligand Efficiency Indices (LEIs). We use a binding efficiency index (BEI) based on the measured binding affinity related to the molecular weight (MW) of the compound combined with surface-binding efficiency index (SEI) based on Polar Surface Area (PSA). We will illustrate the use of these indices, combining three crucial variables (potency, MW and PSA) in a 2D graphical representation of chemical space, to perform a retrospective mapping of SAR data for a current TTR inhibitors database, and we propose prospective strategies to use these efficiency indices and chemico-biological space maps for optimization and drug design efforts for TTR ligands.

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Isatin derivatives, a novel class of transthyretin fibrillogenesis inhibitors

Cited by 48 publications

References 20 publications

Design, synthesis, and QSAR study of novel 2-(2,3-dioxo-2,3-dihydro-1H-indol-1-yl)-N-phenylacetamide derivatives as cytotoxic agents

Design, synthesis, and QSAR study of novel 2-(2,3-dioxo-2,3-dihydro-1H-indol-1-yl)-N-phenylacetamide derivatives as cytotoxic agents

Strategies for Inhibiting Protein Aggregation: Therapeutic Approaches to Protein-Aggregation Diseases

Retrospective Mapping of SAR Data for TTR Protein in Chemico‐Biological Space Using Ligand Efficiency Indices as a Guide to Drug Discovery Strategies

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